Oxygen binding and activation reactions at dimetal sites constitute chemical processes of fundamental interest, because of the implication of these reactions in biology, chemical synthesis, and catalysis. This account collects and discusses studies of O2 binding and/or activation by inequivalent dimetal sites, and it specially focuses on systems in which O2-bound reaction intermediates have been experimentally characterized. Homometallic unsymmetric systems and heterometallic complexes are reviewed, and their chemistry in oxidative transformations is described. Introduction of asymmetry into M2O2 cores poses important challenges to their preparation, and strategies developed to address this problem are discussed. Distinct spectroscopic and chemical properties emerge from these unsymmetric systems.